Asymmetric synthesis of intermediates for retroviral protease inhibitor compounds

ABSTRACT

The disclosure describes an improved process for producing optically active compounds of Formula II or III, which compounds are useful as intermediates for preparing compounds active as inhibitors of retroviral protease enzymes: ##STR1## wherein R 1 , R 50  and Z are described in the specification. The improved process includes either synthesis of diastereomeric iodolactones which are separated prior to conversion to compounds of Formula II or III or synthesis of an epoxide which is converted directly to compounds of Formula II and III.

This is a divisional of application Ser. No. 08/181,924 filed on Jan.14, 1994, now U.S. Pat. No. 5,428,167.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to an improved process for producing opticallyactive compounds which are useful as intermediates for compounds whichare inhibitors of retroviral protease enzymes and anti-HIV agents and tocertain novel intermediate compounds utilized in the novel process.

SUMMARY OF THE INVENTION

It will be appreciated that those skilled in the art recognize that theatoms labelled with an asterisk (*) represent an optically activeasymmetric center.

The invention provides an improved process for producing opticallyactive compounds of Formula II or III, which compounds are useful asintermediates for preparing compounds active as inhibitors of retroviralprotease enzymes: ##STR2## wherein: R₅₀ is a straight or branched (C₁-C₇)alkyl;

Z is a single bond, oxygen or NH;

R₁ is hydrogen; straight or branched (C₁ -C₇)alkyl;

--(CH₂)_(n) -cyclic(C₃ -C₇)alkyl, n=0-4; --(CH₂)_(n) -phenyl, n=0-4; or--(CH₂)_(n) -substituted phenyl, n=0-4, and substituted with F, Cl, Br,I, (C₁ -C₄)alkoxide, straight, branched or cyclic (C₁ -C₆)alkyl orphenyl.

An improved process according to the present invention to produce anoptically active compound according to Formula II comprises:

a) deprotonating a compound of the formula: ##STR3## wherein R₁ ishydrogen; straight or branched (C₁ -C₇)alkyl;

--(CH₂)_(n) -cyclic(C₃ -C₇)alkyl, n=0-4; --(CH₂)_(n) -phenyl, n=0-4; or--(CH₂)_(n) -substituted phenyl, n=0-4, and substituted with F, Cl, Br,I, (C₁ -C₄)alkoxide, straight, branched or cyclic (C₁ -C₆)alkyl orphenyl;

D is (C₁ -C₇)alkyl or --(CH₂)_(n) -phenyl, n=0-4; and

E and G are the same or different and are hydrogen, (C₁ -C₇)alkyl or--(CH₂)_(n) -phenyl, n=0-4; and then alkylating with allyl iodide toobtain a compound of the formula: ##STR4## wherein R₁, D, E, and G areas defined hereinabove; b) hydrolyzing the compound obtained from step ato remove the oxazolidinone portion and obtain a compound of theformula: ##STR5## wherein R₁ is as defined hereinabove; c) reacting thecompound obtained from step b with dimethylamine to obtain a compound ofthe formula: ##STR6## wherein R₁ is as defined hereinabove: d)subjecting the compound obtained from step c to iodolactonizationconditions to obtain a mixture of diastereomers, 3R-cis, 3R-trans, ofthe formula: ##STR7## wherein R₁ is as defined hereinabove; andseparating the isomers to obtain a purified trans-iodolactone (IsomerA); and

e) coupling the purified trans-iodolactone obtained from step d (IsomerA) with a compound of formula: ##STR8## via iodide displacement whereinR₅₀ is a straight or branched (C₁ -C₇)alkyl and Z is a single bond,oxygen or NH; to obtain a compound of the formula: ##STR9## wherein R₁,R₅₀ and Z are as defined hereinabove.

An improved process according to the present invention to produce anoptically active compound according to Formula III, comprises:

a) deprotonating a compound of the formula: ##STR10## wherein R₁ ishydrogen; straight or branched (C₁ -C₇)alkyl; --(CH₂)_(n) -cyclic(C₃-C₇)alkyl, n=0-4; --(CH₂)_(n) -phenyl, n=0-4; or --(CH₂)_(n)-substituted phenyl, n=0-4, and substituted with F, Cl, Br, I, (C₁ -C₄)alkoxide, straight, branched or cyclic (C₁ -C₆)alkyl or phenyl;

D is (C₁ -C₇)alkyl or --(CH₂)_(n) -phenyl, n=0-4; and

E and G are the same or different and are hydrogen, (C₁ -C₇)alkyl or--(CH₂)_(n) -phenyl, n=0-4; and then alkylating with allyl iodide toobtain a compound of the formula: ##STR11## wherein R₁, D, E, and G areas defined hereinabove; b) hydrolyzing the compound obtained from step ato remove the oxazolidinone portion and obtain a compound of theformula: ##STR12## wherein R₁ is as defined hereinabove; c) subjectingthe compound obtained from step b to iodolactonization conditions toobtain a mixture of diastereomers, 3R-cis, 3R-trans, of the formula:##STR13## wherein R₁ is as defined hereinabove; and separating theisomers to obtain a purified cis-iodolactone (isomer B);

d) coupling the purified cis-iodolactone obtained from step c (Isomer B)with a compound of formula: ##STR14## via iodide displacement whereinR₅₀ is a straight or branched (C₁ -C₇)alkyl and Z is a single bond,oxygen or NH; to obtain a compound of the formula: ##STR15## wherein R₁,R₅₀ and Z are as defined hereinabove.

An alternative improved process to obtain a compound of the formula IIor III comprises:

a) deprotonating a compound of the formula: ##STR16## wherein R₁ ishydrogen; straight or branched (C₁ -C₇)alkyl; --(CH₂)_(n) -cyclic(C₃-C₇)alkyl, n=0-4; --(CH₂)_(n) -phenyl, n=0-4; or --(CH₂)_(n)-substituted phenyl, n=0-4, and substituted with F, Cl, Br, I, (C₁-C₄)alkoxide, straight, branched or cyclic (C₁ -C₆)alkyl or phenyl;

D is (C₁ -C₇)alkyl or --(CH₂)_(n) -phenyl, n=0-4; and

E and G are the same or different and are hydrogen, (C₁ -C₇)alkyl or--(CH₂)_(n) -phenyl, n=0-4; and then alkylating with allyl iodide toobtain a compound of the formula: ##STR17## wherein R₁, D, E, G are asdefined hereinabove; b) epoxidizing the compound obtained from step a toobtain a compound of the formula: ##STR18## wherein R₁, D, E, and G areas defined hereinabove; c) coupling the compound obtained from step bwith a compound of the formula: ##STR19## via displacement of theepoxide and concomitant lactonization wherein R₅₀ is a straight orbranched (C₁ -C₇)alkyl and Z is a single bond, oxygen or NH; to obtain adiastereomeric mixture of compounds of the formulae: ##STR20## whereinR₁, R₅₀ and Z are as defined hereinabove; d) separating thediastereomeric mixture obtained from step c to obtain a purifiedcompound of Formula II or a purified compound of Formula III.

The invention also provides an improved process for converting theintermediate compounds of Formula II or Formula III into the opticallyactive retroviral protease inhibitor compounds of formula Ia and Ib:##STR21## wherein: R₅₀ is a straight or branched (C₁ -C₇)alkyl;

Z is a single bond, oxygen or NH;

R₁ is hydrogen; straight or branched (C₁ -C₇)alkyl;

--(CH₂)_(n) -cyclic(C₃ -C₇)alkyl, n=0-4; --(CH₂)_(n) -phenyl, n=0-4; or--(CH₂)_(n) -substituted phenyl, n=0-4, and substituted with F, Cl, Br,I, (C₁ -C₄)alkoxide, straight, branched or cyclic (C₁ -C₆)alkyl orphenyl;

R₆₀ is a straight or branched (C₁ -C₇)alkyl;

--(CH₂)_(n) -cyclic (C₃ -C₇)alkyl, n=0-4; --(CH₂)₂ CONH₂ ; --CH₂ CONH₂ ;--CH₂ OH or --CH(CH₃)OH;

R₇₀ is a moiety of the formula: ##STR22## wherein W₁ is --NH(CH₂)_(j)-phenyl, j=0-1;

--NH(CH₂)_(j) -substituted phenyl, j=0-1, substituted with F, Cl, Br, I,(C₁ -C₄)alkoxide, straight, branched or cyclic (C₁ -C₆)alkyl;--NH(CH₂)_(j) -T, j=0-1, wherein T is selected from piperidinyl,piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl,2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl,pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl,pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl,isoxazolyl, isoazolidinyl, morpholinyl, thiazolyl, thiazolidinyl,isothiazolyl, benzofuranyl, benzodioxanonyl, quinuclidinyl,isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl,thiadiazoyl, benzopyranyl, benzothiapyranyl, benzothiazolyl,benzoxaolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl,benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide,thiamorpholinyl sulfone and oxadiazolyl; or

--NH(CH₂)_(j) -substituted T, j=0-1, T is as defined hereinabove,substituted with F, Cl, I, Br, (C₁ -C₄)alkoxide, or straight, branchedor cyclic (C₁ -C₆)alkyl.

The improved process to produce Ib, comprises:

a) hydrolyzing a compound of Formula III to obtain a compound of theformula: ##STR23## wherein R₁, R₅₀ and Z are as defined hereinabove; b)protecting the alcohol and carboxylic acid functionalities of thecompound obtained from step a to obtain a compound of the formula:##STR24## wherein R₁, R₅₀ and Z are as defined hereinabove and R is astraight or branched (C₁ -C₆)alkyl or phenyl;

c) selectively deprotecting the carboxylic acid functionality of thecompound obtained from step b to obtain a compound of the formula:##STR25## wherein R, R₁, R₅₀ and Z are as defined hereinabove; d)reacting the deprotected carboxylic acid functionality of the compoundobtained from step c with a compound of the formula: ##STR26## whereinR₆₀ is a straight or branched (C₁ -C₇)alkyl;

--(CH₂)_(n) -cyclic (C₃ -C₇)alkyl, n=0-4; --(CH₂)₂ CONH₂ ; --CH₂ CONH₂ ;--CH₂ OH or --CH(CH₃)OH;

R₇₀ is a moiety of the formula: ##STR27## wherein W₁ is --NH(CH₂)_(j)-phenyl, j=0-1;

--NH(CH₂)_(j) -substituted phenyl, j=0-1, substituted with F, Cl, Br, I,(C₁ -C₄)alkoxide, straight, branched or cyclic (C₁ -C₆)alkyl;--NH(CH₂)_(j) -T, j=0-1, wherein T is selected from piperidinyl,piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl,2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl,pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl,pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl,isoxazolyl, isoazolidinyl, morpholinyl, thiazolyl, thiazolidinyl,isothiazolyl, benzofuranyl, benzodioxanonyl, quinuclidinyl,isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl,thiadiazoyl, benzopyranyl, benzothiapyranyl, benzothiazolyl,benzoxaolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl,benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide,thiamorpholinyl sulfone and oxadiazolyl; or

--NH(CH₂)_(j) -substituted T, j=0-1, T is as defined hereinabove,substituted with F, Cl, I, Br, (C₁ -C₄)alkoxide, or straight, branchedor cyclic (C₁ -C₆)alkyl; to obtain a compound of the formula: ##STR28##wherein R, R₁, R₅₀, R₆₀, R₇₀ and Z are as defined hereinabove; and

i) deprotecting the alcohol functionality of the compound obtained fromstep d to obtain the compound of formula Ib.

The improved process to produce Ia, comprises:

a) hydrolyzing a compound of Formula II to obtain a compound of theformula: ##STR29## wherein R₁, R₅₀ and Z are as defined hereinabove; b)protecting the alcohol and carboxylic acid functionalities of thecompound obtained from step a to obtain a compound of the formula:##STR30## wherein R₁, R₅₀ and Z are as defined hereinabove and R is astraight or branched (C₁ -C₆)alkyl or phenyl;

c) selectively deprotecting the carboxylic acid functionality of thecompound obtained from step b to obtain a compound of the formula:##STR31## wherein R, R₁, R₅₀ and Z are as defined hereinabove; d)reacting the deprotected carboxylic acid functionality of the compoundobtained from step c with a compound of the formula: ##STR32## whereinR₆₀ is a straight or branched (C₁ -C₇)alkyl;

--(CH₂)_(n) -cyclic (C₃ -C₇)alkyl, n=0-4; --(CH₂)₂ CONH₂ ; --CH₂ CONH₂ ;--CH₂ OH or --CH(CH₃)OH;

R₇₀ is a moiety of the formula: ##STR33## wherein W₁ is --NH(CH₂)_(j)-phenyl, j=0-1;

--NH(CH₂)_(j) -substituted phenyl, j=0-1, substituted with F, Cl, Br, I,(C₁ -C₄)alkoxide, straight, branched or cyclic (C₁ -C₆)alkyl;

--NH(CH₂)_(j) -T, j=0-1, wherein T is selected from piperidinyl,piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl,2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl,pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl,pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl,isoxazolyl, isoazolidinyl, morpholinyl, thiazolyl, thiazolidinyl,isothiazolyl, benzofuranyl, benzodioxanonyl, quinuclidinyl,isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl,thiadiazoyl, benzopyranyl, benzothiapyranyl, benzothiazolyl,benzoxaolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl,benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide,thiamorpholinyl sulfone and oxadiazolyl; or

--NH(CH₂)_(j) -substituted T, j=0-1, T is as defined hereinabove,substituted with F, Cl, I, Br, (C₁ -C₄)alkoxide, or straight, branchedor cyclic (C₁ -C₆)alkyl; to obtain a compound of the formula: ##STR34##wherein R, R₁, R₅₀, R₆₀, R₇₀ and Z are as defined hereinabove; and

e) deprotecting the alcohol functionality of the compound obtained fromstep d to obtain the compound of formula Ia.

Also included in the present invention are certain novel intermediatecompounds useful as intermediates for producing the retroviral proteaseinhibitor compounds of Formula Ia or Ib. Such intermediate compoundsinclude those of the formula: ##STR35## wherein R₁ is hydrogen; straightor branched (C₁ -C₇) alkyl;

--(CH₂)_(n) -cyclic(C₃ -C₇)alkyl, n=0-4;

--(CH₂)_(n) -phenyl, n=0-4; or

--(CH₂)_(n) -substituted phenyl, n=0-4, and substituted with F, Cl, Br,I, (C₁ -C₄)alkoxide, straight, branched or cyclic (C₁ -C₆)alkyl orphenyl;

D is (C₁ -C₇)alkyl or --(CH₂)_(n) -phenyl, n=0-4;

E and G are the same or different and are hydrogen, (C₁ -C₇)alkyl or--(CH₂)_(n) -phenyl, n=0-4.

Additional novel intermediates according to the present invention usefulfor producing the retroviral protease inhibitor compounds of Formula Iaor Ib include those of the formulae: ##STR36## wherein R₁ is hydrogen;straight or branched (C₁ -C₇)alkyl;

--(CH₂)_(n) -cyclic(C₃ -C₇)alkyl, n=0-4;

--(CH₂)_(n) -phenyl, n=0-4; or

--(CH₂)_(n) -substituted phenyl, n=0-4, and substituted with F, Cl, Br,I, (C₁ -C₄)alkoxide, straight, branched or cyclic (C₁ -C₆)alkyl orphenyl.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The novel process of the present invention will be described in greaterdetail with reference to the following schemes: ##STR37##

The synthesis of (S)-alpha-2-propenylbenzenepropanoic acid, 2, isdescribed in Scheme 1.(S)-2-oxo-3-(1-oxo-3-phenylpropyl)-4-(phenylmethyl)-2-oxazolidinone isdeprotonated with sodium bis(trimethylsilyl)amide (NaHMDS) intetrahydrofuran at -78° C. It is contemplated that other deprotonatingagents known to those skilled in the art may also be employed. Thedeprotonated compound is then alkylated with ally iodide to providecompound 1. It will be appreciated by those skilled in the art thatsubstituted allyl electrophiles may be employed in the place of allyliodide. The oxazolidinone portion of 1 is removed by hydrolysis withlithium hydroxide, hydrogen peroxide in aqueous tetrahydrofuran to giveacid 2. It is contemplated that other hydrolysing agents known to thoseskilled in the art may also be employed.

The synthesis of [3S-[2[alphaS*(1R*,2R*),gammaS*(orR*)],3alpha,4abeta,8abeta]]-N-[1[[(1H-Benzimidazol-2-ylmethyl)amino]carbonyl]-2-methylbutyl]-3-[[(1,1-dimethylethyl)amino]carbonyl]decahydro-gamma-hydroxy-alpha-(phenylmethyl)-2-isoquinolinepentanamide,9, is described in Schemes 2, 3, 4 and 5.

In Scheme 2, acid 2 is subjected to iodolactonization conditions, suchas treatment with iodine, potassium iodide and potassium bicarbonate inaqueous tetrahydrofuran to provide iodolactone, 3, which is a 1:4mixture of isomers (3A-trans:3B-cis). The isomers are purified by knownpurification techniques including, but not limited to, chromatography.The purified major isomer of this reaction, 3B, is treated with[3S-(3alpha,4beta,8abeta)]-N-(1,1-dimethylethyl)-decahydro-3-isoquinolinecarboxamide,product of Reference Example 4, and N,N-diisopropylethylamine inN,N-dimethylformamide to give lactone, 4. Lactone, 4, is hydrolyzed tocompound 5, by reaction with sodium hydroxide in water. It iscontemplated that other hydrolysing agents known to those skilled in theart may also be employed. Compound 5, serves as a branch point forSchemes 3 and 4.

The alcohol and carboxylic acid functionalities of compound 5, areprotected with suitable protecting agents via reaction withchloroisopropyldimethylsilane (IPDMSCl), triethylamine (NEt₃), andN,N-(dimethylamino)pyridine (DMAP) in methylene chloride to givecompound 6. It is contemplated that other suitable carboxylic acid andalcohol protecting agents known to those skilled in the art may also beemployed. The acid functionality of compound 6 is selectivelydeprotected via hydrolysis of the silyl ester by reaction with aceticacid in water, tetrahydrofuran and acetone, to obtain acid, 7. Acid, 7,is coupled to[S-(R*,R*)]-2-amino-N-(1H-benzimidazol-2-ylmethyl)-3-methylpentanamidetris(trifluoroacetate), product of Reference Example 6, by reaction withbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(BOP) and N,N-diisopropylethylamine in methylene chloride to givecompound 8.

The alcohol functionality of compound 8 is deprotected by cleavage ofthe silyl ether by reaction with tetrabutylammonium fluoride (TBAF) intetrahydrofuran or by reaction with acetic acid (HOAc) in water to givecompound 9.

In Scheme 3, the carboxylic acid and alcohol functionalities of compound5, are protected with suitable protecting agents via reaction withtriphenylsilyl chloride (TPSCl), triethylamine andN,N-(dimethylamino)pyridine in methylene chloride to give compound 10.Selective deprotection of the acid functionality of compound 10is byhydrolysis which occurs by reaction with acetic acid in tetrahydrofuran,acetone and water to give acid, 11. It is contemplated that otherhydrolysing agents known to those skilled in the art may also beemployed.

Compound, 11, is coupled with[S-(R*,R*)]-2-amino-N-(1H-benzimidazol-2-ylmethyl)-3-methylpentanamidetris(trifluoroacetate), product of Reference Example 6, by reaction withbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(BOP) and N,N-diisopropylethylamine in methylene chloride to givecompound 12. The alcohol functionality of compound 12 is deprotected bycleavage of the silyl ether by reaction with tetrabutylammonium fluoridein tetrahydrofuran solution to give compound 9. It is contemplated thatother reagents known to those skilled in the art may be utilized forsuch deprotection.

In Scheme 4, the carboxylic acid and alcohol functionalities of compound5, are protected with suitable protection agents for example viareaction with tert-butyldimethylsilyl chloride (TBDMSCl), imidazole andN,N-dimethylformamide to give compound 13, which is not isolated. Thecrude reaction mixture is treated with methyl alcohol to deprotect theacid functionality and provide after isolation acid 14.

Acid, 14, is coupled to[S-(R*,R*)]-2-amino-N-(1H-benzimidazol-2-ylmethyl)-3-methylpentanamidetris(trifluoroacetate), product of Reference Example 6, by reaction withbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(BOP) and N,N-diisopropylethylamine in methylene chloride to givecompound 15. The alcohol functionality of compound 15 is deprotected bycleaving the silyl ether by reaction with tetrabutylammonium fluoride intetrahydrofuran solution or by reaction with acetic acid in water togive compound 9.

In Scheme 5, acid 2 is reacted with dimethylamine, N,N-diisopropylamine,benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(BOP) and 1-hydroxybenzotriazole (HOBT) in methylene chloride to giveamide 16. It will be appreciated by those skilled in the art that otherdialkylamines may be employed in place of dimethylamine to producecorresponding dialkylamides. Reaction of amide 16 underiodolactonization conditions with iodine in wet dimethoxyethane providesiodolactone, 3, as a 17:1 mixture of isomers in this reaction(3A-trans:3B-cis). The isomers are purified by known purificationtechniques, including, but not limited to, chromatography. The purifiedmajor iodolactone, 3A, is reacted with[3S-(3alpha,4abeta,8abeta)]-N-(1,1-dimethylethyl)-decahydro-3-isoquinolinecarboxamide,product of Reference Example 4, in the presence ofN,N-diisopropylethylamine in N,N-dimethylformamide to give lactone, 17,which is hydrolyzed to hydroxyacid 18 by reaction with aqueous sodiumhydroxide.

The carboxylic acid and alcohol functionalities of Compound 18 areprotected with suitable protecting agents for example via reaction withchloroisopropyldimethylsilane (IPDMSCl), triethylamine, andN,N-(dimethylamino)pyridine (DMAP), in methylene chloride to givecompound 19. It will be appreciated by those skilled in the art thatother suitable carboxylic acid and alcohol protecting agents may also beemployed. The carboxylic acid functionality of compound 19 isselectively deprotected to give compound 20 by reaction with acetic acidtetrahydrofuran, acetone and water. It is contemplated that otherselective deprotecting agents known to those skilled in the art may alsobe employed. Compound 20, is coupled to[S-(R*,R*)]-2-amino-N-(1H-benzimidazol-2-ylmethyl)-3-methylpentanamidetris(trifluoroacetate), product of Reference Example 6, by reaction withbenzotriazol-1yloxytris(dimethylamino)phosphonium hexafluorophosphate(BOP) and N,N-diisopropylethylamine in methylene chloride to givecompound 21. The alcohol functionality of compound 21 is deprotected byreaction with tetrabutylammonium fluoride in tetrahydrofuran orhydrolysis with acetic acid in water to give compound 22.

In Scheme 6,-oxazolidinone, 1 is epoxidized via reaction with3-chloroperoxybenzoic acid (m-CPBA), sodium bicarbonate, in methylenechloride to give epoxide, 23, as a 1:1 ratio of diastereomers. Themixture of isomers, 23, is coupled with[3S-(3alpha,4abeta,8abeta)]-N-(1,1-dimethylethyl)-decahydro-3-isoquinolinecarboxamide,product of Reference Example 4, via displacement of the epoxide andconcomitant lactonization to give compounds 4 and 17 in a 1:1 ratio. Thetwo diastereomers are readily separable from one another by knownpurification techniques, for example, flash chromatography on silicagel.

Lactone, 4, is transformed into compound 9 as described previously inSchemes 2, 3, and 4.

Lactone, 17, is transformed into compound 22 as described previously inScheme 5.

The protecting groups used in Schemes 2-6 are:

1. isopropyldimethylsilyl ether and isopropyldimethylsilyl ester, or

2. tert-butyldimethylsilyl ether and tert-butyldimethylsilyl ester, or

3. triphenylsilyl ether and triphenylsilyl ester.

It will be appreciated by those skilled in the art that other carboxylicacid and alcohol protecting groups may similarly be employed.

The following non-limiting examples illustrate the processes of thepresent invention as well as the preparation of novel intermediates.

EXPERIMENTAL REFERENCE EXAMPLE 1(S)-2-Oxo-3-(1-oxo-3-phenylpropyl)-4-(phenylmethyl-2-oxazolidinone

To a -78° C. solution of 25 g (S)-(-)-4-benzyl-2-oxazolidinone in 375 mlof dry tetrahydrofuran is added, dropwise, 57 ml of 2.5M n-butyllithium.The mixture is stirred at -78° C. for 15 minutes, 22 ml ofhydrocinnamoyl chloride is added and the solution is warmed to roomtemperature. The reaction is quenched with water, extracted with ethylacetate, dried and concentrated in vacuo. The residue is recrystallizedwith ethyl acetate/hexane to give 39 g of the desired product, mp92°-93° C.

REFERENCE EXAMPLE 2[3S-(3-alpha,4abeta,8abeta)]-Octahydro-2(1H),3-isoquinolinedicarboxylicacid 1-(phenylmethyl)ester

To a 0° C. solution of 3.0 g of[3S-3alpha,4abeta,8abeta)]-decahydro-3-isoquinolinecarboxylic acid in 75ml of water is added 3.5 ml of 5M sodium hydroxide. After 15 minutes,6.15 g of benzyl chloroformate is added. During the addition the pH ismaintained at >10 with sodium hydroxide. The reaction mixture is stirredat 0° C. for 2 hours, made acidic (pH 2) with 10% hydrochloric acid andextracted with methylene chloride. The organic layer is washed withsaturated sodium chloride, dried, filtered and concentrated in vacuo.The residue is purified twice by chromatography (silica gel; gradientelution 0-20% methyl alcohol/chloroform) to give 2.0 g of the desiredproduct.

REFERENCE EXAMPLE 3[3S-(3alpha,4abeta,8abeta)]-3-[[(1,1-Dimethylethyl)amino]carbonyl]octahydro-2(1)-isoquinolinecarboxylicacid phenylmethyl ester

To a room temperature solution of 0.050 g of product from ReferenceExample 2 in 2 ml of methylene chloride is added 0.090 g ofbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate,hereinafter called BOP, 0.015 g of t-butylamine and 0.159 g oftriethylamine. The reaction is stirred at room temperature for 5 hours,poured into a solution of half saturated sodium chloride, and extractedwith methylene chloride. The organic layer is washed with saturatedsodium chloride, dried, filtered and concentrated in vacuo. The residueis purified by chromatography (silica gel; 20% ethyl acetate/hexane) togive 0.046 g of the desired product as a colorless oil.

REFERENCE EXAMPLE 4[3S-(3alpha,4abeta,8abeta)-N-(1,1-Dimethylethyl)decahydro-3-isoquinolinecarboxamide

To a solution of 0.045 g of product from Reference Example 3 in 1 ml ofethyl alcohol is added 0.010 g of 10% Pd/C and the reaction vessel isfitted with a balloon filled with hydrogen. The reaction is stirred atroom temperature for 3 hours, filtered and concentrated in vacuo. Theresidue is purified by chromatography (silica gel; 10% methylalcohol/chloroform) to give 0.0175 g of product as a colorless oil.

Alternatively, the title compound may be prepared by a one step process.

To a 0° C. solution of 2.0 g of[3S-3alpha,4abeta,8abeta)]-decahydro-3-isoquinolinecarboxylic acid in 40ml of methylene chloride is added 39.91 g of t-butylamine, 14.11 g ofN,N-diisopropylethylamine (Hunig's base), and 6.28 g of BOP in 20 ml ofmethylene chloride. The reaction is stirred at 0° C. for 1 hour followedby 3 hours at room temperature. The mixture is poured into saturatedsodium chloride and extracted with methylene chloride. The organic layeris washed with saturated sodium chloride, dried, filtered andconcentrated in vacuo. The residue is purified by chromatography (silicagel; 10% methyl alcohol/chloroform) to give 3.1 g of the desired productas a tan foam.

REFERENCE EXAMPLE 5[S-(R*,R*)]-[1-[[(1H-Benzimidazol-2-ylmethyl)amino]carbonyl]-2-methylbutyl]carbamicacid 1,1-dimethylethyl ester

To a room temperature solution of 0.505 gN-(tert-butoxycarbonyl)-n-isoleucine in 10 ml of methylene chloride isadded, in the following order, 0.50 g of 2-(aminomethyl)benzimidazoledihydrochloride hydrate, 1.07 g of BOP and 0.850 g of triethylamine. Thereaction is stirred at room temperature for 2 hours, diluted withmethylene chloride, and washed with saturated sodium chloride. Theorganic layer is dried, filtered, and concentrated in vacuo.Purification by chromatography (silica gel; 70% ethyl acetate/hexane)gives 0.669 g of the desired product.

REFERENCE EXAMPLE 6[S-(R*,R*)]-2-Amino-N-(1H-benimidazol-2-ylmethyl)-3-methylpentanamidetris(trifluoroacetate)

To 0.588 g of product from Reference Example 5 in 6 ml of methylenechloride is added 1.3 ml of trifluoroacetic acid (TFA). The reaction isheated at 80°-90° C. for 41/2 hours and concentrated in vacuo to givethe desired product.

EXAMPLE 1[S-(R*,R*)]-3-[1-Oxo-2-(phenylmethyl)-4-pentenyl]-4-(phenylmethyl)-2-oxazolidinone

To a -78° C. solution of 339 ml of 1M sodium bis(trimethylsilyl)amine in300 ml of tetrahydrofuran is added, dropwise over 30 minutes, 100.0 g of(S)-2-oxo-3-(1-oxo-3-phenylpropyl)-4-(phenylmethyl)-2-oxazolidinone,product from Reference Example 1, in 600 ml of tetrahydrofuran. Themixture is stirred at -78° C. for 15 minutes followed by the addition,over 5 minutes, of 108.6 g of allyl iodide in 300 ml of tetrahydrofuran.The reaction is stirred at -78° C. for 1.75 hours, poured into 1.2 L ofsaturated ammonium chloride and extracted with methylene chloride. Theorganic layer is washed with saturated sodium chloride, dried andconcentrated in vacuo. The residue is purified by chromatography (Silicagel: 15-50% ethyl acetate/hexane) to give 98.3 g (87%) of the desiredproduct as a pale yellow solid.

[α]_(D) ²⁵ =+121 (c=1.1, CHCl₃). Calcd for C₂₂ H₂₃ NO₃ : C=75.62;H=6.63; N=4.01 Found C=75.51; H=6.70; N=4.02

EXAMPLE 2 (S)-alpha-2-Propenyl-benzenepropanoic acid

To a 0° C. solution of 45.0 g of product from Example 1 in 637 ml oftetrahydrofuran and 112 ml of water is added 59 ml of 30% hydrogenperoxide and 8.65 g of lithium hydroxide in 100 ml of water. Thereaction is stirred for 3 hours at 0° C. A solution of 58 g of sodiumsulfite in 200 ml of water is added to the reaction, stirring iscontinued for 5 minutes and the mixture is concentrated in vacuo. Theresidue is extracted with water and methylene chloride. The aqueouslayer is cooled to 0° C., made acidic to pH 3 with concentratedhydrochloric acid and extracted with methylene chloride. The methylenechloride layer is washed with saturated sodium chloride, dried, andconcentrated in vacuo to give 23.26 g (95%) of the desired product as apale yellow oil.

[α]_(D) ²⁵ =+23 (c=1.2, CHCl₃). Calcd for C₁₂ H₁₄ O₂ : C=75.76; H=7.42Found C=75.56; H=7.18

EXAMPLE 3(3R-cis)-Dihydro-5-(iodomethyl)-3-(phenylmethyl)-2-(3H)-furan-2-one(Isomer B)(3R-trans)-Dihydro-5-iodomethyl-3-(phenylmethyl)-2(3H)-furan-2-one(Isomer A))

To a room temperature solution of 5.19 g of product from Example 2 in268 ml of tetrahydrofuran and 132 ml of water is added 13.66 g ofpotassium hydrogen carbonate, 83.09 g of iodine, and 36.23 g ofpotassium iodide. The reaction mixture is maintained at roomtemperature, protected from light, for 5 hours followed by dilution with1 L of ethyl acetate. The organic layer is washed with saturated sodiumbicarbonate, 10% aqueous sodium thiosulfate, dried and concentrated invacuo. The residue is purified by chromatography (silica gel: 10% ethylacetate/hexane) to give 2.13 g (25%) of the minor product (Isomer A) and4.36 g (51%) of the major product (Isomer B). Ratio of isomer A:B is 1:2

Isomer A:

¹ H NMR(CDCl₃):δ 7.38-7.20(m,5H); 4.35-4.28(m,1H); 3.39-3.02(m,4H);2.85-2.75(m,1H); 2.24-2.06(m,2H).

Isomer B:

¹ H NMR(CDCl₃):δ 7.35-7.27(m,5H); 4.35-4.25(m,1H); 3.40-2.92(m,4H);2.81-2.75(m,1H); 2.55-2.45(m,1H); 1.75-1.55 (m,1H).

EXAMPLE 4[3S-[2(2S*,4S*),3alpha,4abeta,8abeta[[-N-(1,1-Dimethylethyl)octahydro-2-[[tetrahydro-5-oxo-4-(phenylmethyl)-2-furanyl]methyl]-3-isoquinolinecarboxamide

To a solution of 0.40 g of Isomer B from Example 3 in 10 ml ofN,N-dimethylformamide and 0.332 g of[3S-(3alpha,4abeta,8abeta)]-N-(1,1-dimethylethyl)-decahydro-3-isoquinolinecarboxamide,product from Reference Example 4, is added 242 microliter of N,N-diisopropylethylamine, herinafter called Hunig's base. The reactionmixture is heated at 95° C. for 20 hours, cooled and diluted withsaturated aqueous sodium bicarbonate. The aqueous layer is extractedwith ethyl acetate, dried and concentrated in vacuo. The residue ispurified by chromatography (silica gel: 20-27% ethyl acetate/hexane) togive 0.308 g of the desired product as a colorless foam.

¹ H NMR(CDCl₃):δ 7.30-7.15(m,6H); 6.65(s,1H); 4.52-4.47(m,1H);3.25-3.20(m,1H); 2.95-2.72(m,3H); 2.60-2.49 (m,2H); 2.30-2.14 (m,4H);1.83-1.15 (m,11H); 1.31(s,9H).

EXAMPLE 5[3S-[2[S*(S*)],3alpha,4abeta,8abeta]]-3-[[(1,1-Dimethylethyl)amino]carbonyl]octahydro-gamma-hydroxy-alpha-(phenylmethyl)-2(1H)-isoquinolinepentanoicacid

To a solution of 0.370 g of product from Example 4 dissolved in 4 ml ofmethyl alcohol is added 1.08 ml of 1M sodium hydroxide in water. Themixture is stirred at room temperature for 3.25 hours, diluted withethyl acetate and the aqueous phase is neutralized to pH 7 with 10%aqueous hydrochloric acid. The separated aqueous layer is extracted withethyl acetate and the organic layers are combined. The organic layer iswashed with saturated sodium chloride, dried and concentrated in vacuoto give 0.39 g of the desired product which is used directly in the nextreaction.

EXAMPLE 6[3S-[2[S*(S*)],3alpha,4abeta,8abeta]]-3-[[(1,1-Dimethylethyl)amino]carbonyl]-gamma-[[dimethyl(1-methylethyl)silyl]oxy]octahydro-alpha-(phenylmethyl)-2(1H)-isoquinolinepentanoicacid dimethyl(1-methylethyl)silyl ester

To a solution of 0.208 g of product from Example 5 in 5 ml of methylenechloride is added 0.003 g of 4-(dimethylamino)pyridine, 326 microliterof triethylamine, and 221 microliter of chlorodimethylisopropylsilane.The reaction is stirred for 17 hours, diluted with saturated sodiumchloride and saturated aqueous sodium bicarbonate, and extracted withmethylene chloride. The combined organic layers are washed withsaturated sodium chloride, dried and concentrated to give 0.34 g of thedesired product which is used directly in the next reaction.

EXAMPLE 7[3S-[2[S*(S*)],3alpha,4abeta,8abeta]]-3[[(1,1-Dimethylethyl)amino]carbonyl]-gamma-[[dimethyl(1-methylethyl)silyl]oxy]octahydro-alpha-(phenylmethyl)-2(1H)-isoquinolinepentanoicacid

A 1:1 solution of water and acetone is prepared. Glacial acetic acid isadded to adjust the pH to 5.

To a 0° C. solution of 0.30 g of product from Example 6 in 3 ml oftetrahydrofuran is added 0.75 ml of the acetone/water/acetic acidsolution prepared above. The reaction is stirred at 0° C. for 30 minutesfollowed by stirring at room temperature for 1.25 hours. The mixture isconcentrated in vacuo, toluene is added and the mixture isreconcentrated to remove the residual water and acetic acid. Theproduct, 0.30 g, is isolated and used directly in the next reaction.

EXAMPLE 8[3S-[2[2S*,4S*(1R*,2R*)],3alpha,4abeta,8abeta]]-2-[5[[1-[[(1H-benzimidazol-2-ylmethyl)amino]carbonyl-2-methylbutyl]amino]-2-[[dimethyl(1-methylethyl)silyl]oxy]-5-oxo-4-(phenylmethyl)pentyl]-N-(1,1-dimethylethyl)decahydro-3-isoquinolinecarboxamide

To a solution of 0.25 g of product from Example 7 in 7 ml of methylenechloride is added 799 microliter of Hunig's base, 0.553 g of[S-(R*,R*)]-2-amino-N-(1H-benzimidazol-2-ylmethyl)-3-methylpentanamidetris(trifluroroacetate), product from Reference Example 6, and 0.405 gof BOP. The reaction mixture is stirred at room temperature for 17 hoursfollowed by dilution with half saturated sodium chloride and extractionwith methylene chloride. The organic layers are washed with saturatedsodium chloride, dried and concentrated in vacuo. The residue ispurified by chromatography (silica gel: 5% methyl alcohol/chloroform) togive 0.282 g of the desired product as a colorless foam.

¹ H NMR(CDCl₃):δ 10.51(s,1H); 7.75(br s,1H); 7.47(br s,1H);7.30-7.18(m,7H); 6.97(br s,2H); 6.35(s,1H); 5.45(br s,1H);4.79-4.70(m,1H); 4.19(t,1H); 4.10-4.04(m,1H); 3.92-3.85(m,1H);2.90-2.30(m,4H); 2.20-1.15(m,21H); 1.44(s,9H); 1.07-0.8(m,12H); 0.15(s,3H); 0.07 (s,3H). MS(FAB): m/z 787 (M⁺ +H).

EXAMPLE 9[3S-[2(alphaS*(1R*,2R*),gammaR*],3alpha,4abeta,8abeta]]-N-[1[[(1H-Benzimidazol-2-ylmethyl)amino]carbonyl]-2-methylbutyl]-3-[[(1,1-dimethylethyl)amino]carbonyl]decahydro-gamma-hydroxy-alpha-(phenylmethyl)-2-isoquinolinepentanamide

To a 0.025 g solution of product from Example 8 in 1 ml oftetrahydrofuran is added 0.32 ml of 1M tetrabutylammonium fluoride,hereinafter called TBAF, in tetrahydrofuran. The reaction is stirred for30 minutes, diluted with water and the pH is adjusted to 5, andextracted with chloroform. The organic layers are washed with saturatedsodium chloride, dried and concentrated in vacuo. The residue ispurified by chromatography (silica gel: 10% methyl alcohol/chloroform)to give 0.0181 g of the desired product.

MS (FAB):m/z 687 (M⁺ +H) . ¹ H NMR(CDCl₃):δ 7.57(brs,2H); 7.34(brs,1H);7.24-7.18(m,2H); 7.14-7.00(m,6H); 6.91(brs,1H); 6.18(s,1H);4.68-4.42(m,2H); 4.23(t,1H); 3.80-3.69(m,2H); 2.94-1.00(24H);1.32(s,9H); 0.89-0.77 (m,6H).

EXAMPLE 10[3S-[2[S*(S*)],3alpha,4abeta,8abeta]]-3-[[(1,1-Dimethylethyl)amino]carbonyl]octahydro-alpha-(phenylmethyl)-gamma-[(triphenylsilyl)oxy]-2(1H)-isoquinolinepentanoicacid triphenylsilyl ester

The title compound is prepared by the procedure of Example 6 using 0.193g of product of Example 5 in 5 ml of methylene chloride, 303 microliterof triethylamine, 0.0027 g of DMAP and 0.384 g of triphenylsilylchloride to give 0.534 g of the desired product which is used directlyin the next reaction.

EXAMPLE 11[3S-[2[S*(S*)],3alpha,4abeta,8abeta]]-3[[(1,1-Dimethylethyl)amino]carbonyl]octahydro-alpha-(phenylmethyl)-gamma-[(triphenylsilyl)oxy]-2(1H)-isoquinolinepentanoicacid

The title compound is prepared by the procedure of Example 7 using 0.42g of product from Example 10 in 2.5 ml of tetrahydrofuran, 1.0 ml ofacetone/water/acetic acid solution to give 0.233 g of the desiredproduct which is used directly in the next reaction.

EXAMPLE 12[3S-[2[2S*,4S*(1R*,2R*)],3alpha,4abeta,8abeta]]-2-[5-[[1-[[(1H-benzimidazol-2-ylmethyl)amino]carbonyl]-2-methylbutyl]amino]-5-oxo-4-(phenylmethyl)-2-[(triphenylsilyl)oxy]pentyl]-3-isoquinolinecarboxamide

The title compound is prepared by the procedure of Example 8 using 0.305g of product from Example 11 in 6 ml of methylene chloride, 756microliter of N,N-diisoprpylethylamine, 0.523 g of[S-(R*,R*)]-2-amino-N-(1H-benzimidazol-2-ylmethyl)-3-methylpentanamidetris(trifluroroacetate), product of Reference Example 6, and 0.384 g ofBOP to give 0.242 g of the desired product after chromatography.

MS(FAB): m/z 945 (M⁺ +H).

EXAMPLE 13[3S-[2(alphaS*(1R*,2R*),gammaR*],3alpha,4abeta,8abeta]]-N-[1[[(1H-Benzimidazol-2-ylmethyl)amino]carbonyl]-2-methylbutyl]-3-[[(1,1-dimethylethyl)amino]carbonyl]decahydro-gamma-hydroxy-alpha-(phenylmethyl)-2-isoquinolinepentanamide

The title compound is prepared by the procedure of Example 9 using 0.032g of product from Example 12 in 1 ml of tetrahydrofuran, 0.34 ml of 1MTBAF solution to give 0.028 g of the desired product.

MS (FAB):m/z 687 (M⁺ +H). ¹ H NMR(CDCl₃):δ 7.57(brs,2H); 7.34(brs,1H);7.24-7.18(m,2H); 7.14-7.00(m,6H); 6.91(brs,1H); 6.18(s,1H);4.68-4.42(m,2H); 4.23(t,1H); 3.80-3.69(m,2H); 2.94-1.00(24H);1.32(s,9H); 0.89-0.77 (m, 6H).

EXAMPLE 14[3S-[2[S*(S*)],3alpha,4abeta,8abeta]]-3-[[(1,1-dimethylethyl)amino]carbonyl]-gamma-[[(1,1-dimethylethyl)dimethylsilyl]oxy]octahydro-alpha-(phenylmethyl)-2(1H)-isoquinolinepentanoicacid (1,1-dimethylethyl)dimethylsilyl ester

To 0.222 g of product from Example 5 in 3 ml of N,N-dimethylformamide isadded 0.136 g of imidazole and 0.263 g of t-butyldimethylsilyl chloride.The reaction is stirred at room temperature for 16 hours andconcentrated in vacuo and used in the following reaction.

EXAMPLE 15[3S-[2[S*(S*)],3alpha,4abeta,8abeta]]-3-[[(1,1-dimethylethyl)amino]carbonyl]-gamma-[[(1,1-dimethylethyl)dimethylsilyl]oxy]octahydro-alpha-(phenylmethyl)-2(1H)-isoquinolinepentanoicacid

The crude reaction mixture from Example 14 is stirred with 10 ml ofmethyl alcohol at room temperature for 4.5 hours. The mixture isconcentrated in vacuo, diluted with water, and extracted with ethylacetate. The organic layer is washed with saturated sodium chloride,dried and concentrated in vacuo. The residue is used in the followingreaction.

MS(FAB): m/z 559 (M⁺ +H).

EXAMPLE 16[3S-[2[gammaS*,alphaS*(1R*,2R*),3alpha,4abeta,8abeta]]-N-[1-[[(1H-Benzimidazol-2-ylmethyl)amino]carbonyl]-2-methylbutyl]-3-[[(1,1-dimethylethyl)amino]carbonyl]-gamma-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3,4,4a,5,6,7,8,8a-octahydro-alpha-(phenylmethyl)-2(1H)-isoquinolinepentanamide

The title compound is prepared by the procedure of Example 8 using 0.278g of product from Example 15, 0.599 g of[S-(R*,R*)]-2-amino-N-(1H-benzimidazol-2-ylmethyl)-3-methylpentanamidetris(trifluoroacetate), product of Reference Example 6, 0.440 g of BOP,0.643 g of Hunig's base and 7 ml of methylene chloride to give 0.294 gof the desired product.

MS(FAB): m/z 801 (M⁺ +H).

EXAMPLE 17[3S-[2[alphaS*(1R*,2R*),gammaR*],3alpha,4abeta,8abeta]]-N-[1[[(1H-Benzimidazol-2ylmethyl)amino]carbonyl]-2-methylbutyl]-3[[(1,1-dimethylethyl)amino]carbonyl]decahydro-gamma-hydroxy-alpha-(phenylmethyl)-2-isoquinolinepentanamide

The title compound is prepared by the procedure of Example 9 using 0.050g of product from Example 16, 1.24 ml of 1M TBAF and 2 ml oftetrahydrofuran to give 0.050 g of the desired product.

MS(FAB):m/z 687 (M⁺ +H).

¹ H NMR (CDCl₃):δ 7.57 (brs, 2H); 7.34(brs,1H); 7.24-7.18(m,2H);7.14-7.00(m,6H); 6.91(brs,1H); 6.18(s,1H); 4.68-4.42(m,2H); 4.23(t,1H);3.80-3.69(m,2H); 2.94-1.00(24H); 1.32(s,9H); 0.89-0.77 (m, 6H).

EXAMPLE 18 N,N-Dimethyl-alpha-2-propenylbenzenepropanamide

To a 0° C. solution of 22.95 g of product from Example 2 in 550 ml ofmethylene chloride is added 9.68 g of dimethylamine hydrochloride and58.69 g of BOP. Let stir a few minutes and then add 1.0 g of1-hydroxybenzotriazole hydrate (HOBT) and 155.9 g of Hunig's base. Thereaction is stirred in the cold for 7 hours then allowed to warm to roomtemperature overnight. The reaction is diluted with half saturatedsodium chloride and extracted with methylene chloride. The organic layeris washed with saturated sodium chloride, dried and concentrated invacuo. The residue is purified by chromatography (silica gel: 7-30%ethyl acetate/hexane) to give 24.68 g of the desired product.

MS(CI):m/z 217(M⁺). [α]_(D) ²⁵ =+38 (C=1.1, CHCl₃).

EXAMPLE 19(3R-trans)-Dihydro-5-iodomethyl-3-(phenylmethyl)-2(3H)-furan-2-one(Isomer A)(3R-cis)-Dihydro-5-(iodomethyl)-3-(phenylmethyl)-2(3H)-furan-2-one(Isomer B)

To 24 g of product from Example 18 is added 200 ml of dimethoxyethaneand 200 ml of water. The solution is stirred and cooled at -20° C., inthe dark, for 30 minutes. Iodine, 33.64 g, is added and the stirring at-20° C. continued for 5 hours followed by stirring at room temperaturefor 3 days. The reaction is diluted with 1 L of ethyl acetate, washedwith 1 L of 10% sodium bicarbonate and is extracted with ethyl acetate.The organic layer is washed with sodium bicarbonate, dried, andconcentrated in vacuo. The residue is puriied by repeated chromatography(silica gel: 5-10% ethyl acetate/hexane) to give 27.3 g of the isomerproduct (A) and 1.6 g of isomer product (B). Ratio of isomers (A:B) fromthis reaction is 17:1. The isomers were also made in Example 3 and theratio (A:B) is 1:2.

EXAMPLE 20[3S-[2(2R*,4S*),3alpha,4abeta,8abeta]]-N-(1,1-Dimethylethyl)decahydro-2-[[tetrahydro-5-oxo-4-(phenylmethyl)-2-furanyl]methyl]-3-isoquinolinecarboxamide

The title compound is prepared by the procedure of Example 4 using 27 gof product from Example 19, 20.36 of[3S-(3alpha,4abeta,8abeta)]-N-(1,1-dimethylethyl)decahydro-3-isoquinolinecarboxamide,product of Reference Example 4, 600 ml of N,N-dimethylformamide and16.36 ml of Hunigs base to give 10.3 g of the desired product afterpurification by chromatography.

MS(FAB):m/z 427 (M⁺ +H). [α]_(D) ²⁵ =-69 (c=1.1, CHCl₃).

EXAMPLE 21[3S-[2[R*(S*)],3alpha,4abeta,8abeta]]-3-[[(1,1-Dimethylethyl)amino]carbonyl]octahydro-gamma-hydroxy-alpha-(phenylmethyl)-2(1H)-isoquinolinepentanoicacid

The title compound is prepared by the procedure of Example 5 using 0.25g of product from Example 20, 0.73 ml of sodium hydroxide in water and2.5 ml of methyl alcohol to give 0.270 g of the product which is useddirectly in the next reaction.

EXAMPLE 22[3S-[2[R*(S*)],3alpha,4abeta,8abeta]]-3-[[(1,1-Dimethylethyl)amino]carbonyl]-gamma-[[dimethyl(1-methylethyl)silyl]oxy]octahydro-alpha-(phenylmethyl)-2(1H)-isoquinolinepentanoicacid dimethyl(1-methylethyl)silyl ester

The title compound is prepared by the procedure of Example 6 using 10.0g of product from Example 21, 261 ml of methylene chloride, 0.143 g ofDMAP, 16.33 ml of triethylamine and 11.07 ml ofchlorodimethylisopropylsilane to give the desired product which is useddirectly in the next reaction.

MS(FAB):m/z 545 (M⁺ +H-C₅ H₁₃ Si). [α]_(D) ²⁵ =-31+1 (c=1.2)

EXAMPLE 23[3S-[2[R*(S*)],3alpha,4abeta,8abeta]]-3-[[(1,1-Dimethylethyl)amino]carbonyl]-gamma-[[dimethyl(1-methylethyl)silyl]oxy]octahydro-alpha-(phenylmethyl)-2(1H)-isoquinolinepentanoicacid

The title compound is prepared by the procedure of Example 7 using 15.12g of product from Example 22, 152 ml of tetrahydrofuran and 39 ml ofacetone/water/acetic acid (pH=4) to give the desired product which isused directly in the next reaction.

MS(FAB):m/z 545 (M⁺ +H).

EXAMPLE 24[3S-[2[2S*,4R*(1R*,2R*)],3alpha,4abeta,8abeta]]-2-[5-[[1-[[(1H-Benzimidazol-2-ylmethyl)amino]-carbonyl]-2-methylbutyl]amino]-2-[[dimethyl(1-methylethyl)silyl]oxy]-5-oxo-4-(phenylmethyl)pentyl]-N-(1,1dimethylethyl)decahydro-3-isoquinolinecarboxamide

The title compound is prepared by the procedure of Example 8 using 12.77g of product from Example 23, 365 ml of methylene chloride, 28.24 g of[S-(R*,R*)]-2-amino-N-(1H-benzimidazol-2-ylmethyl)-3-methylpentanamidetris(trifluroroacetate), (prepared by the procedure described in SerialNo. 991,876, Example 12), 40.83 ml of Hunigs base and 2.71 g of BOP togive 5.4 g of the desired product.

MS(FAB):m/z 787 (M⁺ +H).

EXAMPLE 25[3S-[2[alphaS*(1R*,2R*),gammaS*]3alpha,4abeta,8abeta]]-N-[1-[[(1H-Benzimidazol-2-ylmethyl)amino]carbonyl]-2-methylbutyl]-3-[[(1,1-dimethylethyl)amino]carbonyl]decahydro-gamma-hydroxy-alpha-(phenylmethyl)-2isoquinolinepentanamide

The title compound is prepared by the procedure of Example 9 using 5.3 gof product from Example 24, 200 ml of tetrahydrofuran, and 67.33 g ofTBAF to give 2.53 g of the desired product.

¹ H NMR(CDCl₃)δ 7.58(brs,2H); 7.30-7.21(m,2H); 7.15-7.00(m,6H);6.74(brs,1H); 6.12(brs,1H); 4.72-4.17 (m, 3H); 3.84-3.68 (m, 1H);3.25-3.11 (m, 1H); 2.91-1.0(m,24H); 1.35(s,9H); 0.92-0.75(m,6H).MS(FAB):m/z 687 (M⁺ +H).

EXAMPLE 26[2R-[2R*(4S*),2(R*)]]-3-[2-(Oxiranylmethyl)-1-oxo-3-phenylpropyl]-4-(phenylmethyl)-2-oxazolidinoneand[2R-[2R*(4S*),2(S*)]]-3-[2-(Oxiranylmethyl)-1-oxo-3-phenylpropyl]-4-(phenylmethyl)-2-oxazolidinone

To a 0° C. solution of 1.0 g of product from Example 1, 25 ml ofmethylene chloride, and 0.721 g of sodium bicarbonate is added 1.41 g ofm-chloroperbenzoic acid. The reaction is stirred at 0° C. for 3 hoursfollowed by room temperature stirring for 67 hours. The mixture isdiluted with methylene chloride and water and the layers are separated.The organic layer is washed with saturated sodium chloride, dried andconcentrated in vacuo. The residue is purified by chromatography (silicagel: 20% ethyl acetate/hexane) to give 0.81 g of the desired product.

MS(EI):m/z 365 (M⁺). [α]_(D) ²⁵ =+101+1 (CHCl₃).

EXAMPLE 27[3S-[2[2S*,4S*),3alpha,4abeta,8abeta]]-N-(1,1-Dimethylethyl)decahydro-2-[[tetrahydro-5-oxo-4-(phenylmethyl)-2-furanyl]methyl]-3-isoquinolinecarboxamideand[3S-[2[2R*,4S*),3alpha,4abeta,8abeta]]-N-(1,1-Dimethylethyl)decahydro-2-[[tetrahydro-5-oxo-4-(phenylmethyl)-2-furanyl]methyl]-3-isoquinolinecarboxamide

To 1.0 g of product from Example 26 is added 1.53 g of[3S-(3alpha,4abeta,8abeta)]-N-(1,1-dimethylethyl)decahydro-3-isoquinolinecarboxamide,product from Reference Example 4, and 30 ml of ethyl alcohol. Thereaction mixture is heated at reflux temperature 48 hours thenconcentrated in vacuo and stored in the freezer. The residue is purifiedby chromatography (silica gel: 20-27% ethyl acetate/hexane) to give0.723 g of a 1:1 mixture of isomers. The mixture is further purified bychromatography to give:

[3S-[2(2S*,4S*),3alpha,4abeta,4abeta]]-N-(1,1-dimethylethyl)octahydro-2-[[tetrahydro-5-oxo-4-(phenylmethyl)-2-furanyl]methyl]-3-isoquinolinecarboxamide,identical product as product from Example 4, and

[3S-[2(2R*,4S*),3alpha,4abeta,8abeta]]-N-(1,1-dimethylethyl)decahydro-2-[[tetrahydro-5-oxo-4-(phenylmethyl)-2-furanyl]methyl-3-isoquinolinecarboxamide,identical product as product from Example 20.

What is claimed is:
 1. A method of making a compound of formula III: ##STR38## wherein: R₅₀ is a straight or branched (C₁ -C₇)alkyl;Z is a single bond, oxygen or NH; R₁ is hydrogen; straight or branched (C₁ -C₇)alkyl; --(CH₂)_(n) -cyclic(C₃ -C₇)alkyl, n=0-4; --(CH₂)_(n) -phenyl, n=0-4; or --(CH₂)_(n) -substituted phenyl, n=0-4, and substituted with F, Cl, Br, I, (C₁ -C₄)alkoxide, straight or branched (C₁ -C₆)alkyl or (C₃ -C₆)cycloalkyl which comprises:a) deprotonating a compound of the formula: ##STR39## wherein R₁ is as defined hereinabove; D is (C₁ -C₇)alkyl or --(CH₂)_(n) -phenyl, n=0-4; and E and G are the same or different and are hydrogen, (C₁ -C₇)alkyl or --(CH₂)_(n) -phenyl, n=0-4; and then alkylating with allyl iodide to obtain a compound of the formula: ##STR40## wherein R₁, D, E, and G are as defined hereinabove; b) hydrolyzing the compound obtained from step a to remove the oxazolidinone portion and obtain a compound of the formula: ##STR41## wherein R₁ is as defined hereinabove; c) subjecting the compound obtained from step b to iodolactonization conditions to obtain a mixture of diastereomers, 3R-cis, 3R-trans, of the formula: ##STR42## wherein R₁ is as defined hereinabove and separating the isomers to obtain a purified cis-iodolactone (isomer B); andd) coupling the purified cis-iodolactone (Isomer B) obtained from step c with a compound of formula: ##STR43## via iodide displacement wherein R₅₀ and Z are as defined hereinabove; and obtaining a compound of formula III.
 2. The method according to claim 1 further comprising:a) hydrolyzing the compound of Formula III to obtain a compound of the formula: ##STR44## wherein R₁, R₅₀ and Z are as defined hereinabove; b) protecting the alcohol and carboxylic acid functionalities of the compound obtained from step a to obtain a compound of the formula: ##STR45## wherein R₁, R₅₀ and Z are as defined hereinabove and R is a straight or branched (C₁ -C₆) alkyl or phenyl; c) selectively deprotecting the carboxylic acid functionality of the compound obtained from step b to obtain a compound of the formula: ##STR46## wherein R, R₁, R₅₀ and Z are as defined hereinabove; d) reacting the deprotected carboxylic acid functionality of the compound obtained from step c with a compound of the formula: ##STR47## wherein R₆₀ is a straight or branched (C₁ -C₇)alkyl; --(CH₂)_(n) -cyclic (C₃ -C₇)alkyl, n=0-4; --(CH₂)₂ CONH₂ ; --CH₂ CONH₂ ; --CH₂ OH or --CH(CH₃ OH; and R₇₀ is a moiety of the formula: ##STR48## wherein W₁ is --NH(CH₂)_(j) -phenyl, j=0-1; --NH(CH₂)_(j) -substituted phenyl, j=0-1, substituted with F, Cl, Br, I, (C₁ -C₄)alkoxide, straight, branched or cyclic (C₁ -C₆)alkyl; --NH(CH₂)_(j) -T, j=0-1, wherein T is selected from piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, benzofuranyl, benzodioxanonyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiapyranyl, benzothiazolyl, benzoxaolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone and oxadiazolyl; or --NH(CH₂)_(j) -substituted T, j=0-1, T is as defined hereinabove, substituted with F, Cl, I, Br, (C₁ -C₄)alkoxide, or straight, branched or cyclic (C₁ -C₆)alkyl; to obtain a compound of the formula: ##STR49## wherein R, R₁, R₅₀, R₆₀, R₇₀ and Z are as defined hereinabove; and e) deprotecting the alcohol functionality of the compound obtained from step d to obtain the compound of formula Ib: ##STR50## wherein R₁, R₅₀, R₆₀, R₇₀ and Z are as defined hereinabove. 